Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis

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Post-natal nutrition, intestinal dysbiosis and pulmonary hypertension in premature infants: the role of the developing gut-lung axis Abstract Poor growth in the first weeks and months of life is very common in very premature infants with up to 80% of extremely premature infants dropping below the 10th percentile for weight during hospitalization in the Neonatal Intensive Care Unit, a complication referred to as post-natal growth restriction (PNGR). As emphasis has shifted in the last decades from survival to improving outcomes, it has become clear that PNGR is associated with increased risk of much of the morbidity associated with prematurity including pulmonary hypertension (PH), neurodevelopmental delays, necrotizing enterocolitis, sepsis, retinopathy of prematurity, and chronic lung disease (also known as bronchopulmonary dysplasia). Furthermore PNGR in premature infants is also associated with many adult diseases that have been demonstrated to result from fetal growth restriction in term infants including metabolic syndrome, obesity, and hypertension. Simply maximizing caloric intake in the first weeks of life has been somewhat helpful, however PNGR remains very common due to the incredible challenges associated with immaturity of the gastrointestinal tract. We propose novel studies in an animal model of PNGR to discover the mechanisms by which PNGR triggers PH (the most compelling clinical example of alteration of the developing gut-lung axis). We utilize a rat model of PNGR based upon manipulation of the number of pups cared for by a single dam. The PH phenotype associated with PNGR is worsened by exposure to hyperoxia mimicking a common clinical situation (the extremely premature infant with severe lung disease and poor growth). We present preliminary data supporting two groundbreaking observations: first, that PNGR is associated with intestinal dysbiosis and that administration of probiotic microbes prevents PNGR-associated PH and second, that enhanced nutrition is protective against the damaging effect of hyperoxia. In aim 1 we propose experiments to define the developmental window in which probiotics or enhanced nutrition prevent PH. In aim 2 we propose to determine whether the TLR4/MyD88/NFκB pathway is essential in this model. Our novel observation that Enterobacteriaceae are significantly increased in the small intestine with PNGR suggests the potential role of TLR4 in the developing gut-lung axis as the cell wall of these Gram negative organisms contains abundant lipo-polysaccharide (one of the key pathogen associated molecular patterns recognized by TLR4). A mechanistic understanding of these processes is essential to prevention of both infant and adult complications of PNGR.